Lipid catabolism inhibition sensitizes prostate cancer cells to antiandrogen blockade

Abstract

Prostate cancer (PCa) is the most common malignancy among Western men and the second leading-cause of cancer related deaths. For men who develop metastatic castration resistant PCa (mCRPC), survival is limited, making the identification of novel therapies for mCRPC critical. We have found that deficient lipid oxidation via carnitine palmitoyltransferase (CPT1) results in decreased growth and invasion, underscoring the role of lipid oxidation to fuel PCa growth. Using immunohistochemistry we have found that the CPT1A isoform is abundant in PCa compared to benign tissue (n=39, p<0.001) especially in those with high-grade tumors. Since lipid oxidation is stimulated by androgens, we have evaluated the synergistic effects of combining CPT1A inhibition and anti-androgen therapy. Mechanistically, we have found that decreased CPT1A expression is associated with decreased AKT content and activation, likely driven by a breakdown of membrane phospholipids and activation of the INPP5K phosphatase. This results in increased androgen receptor (AR) action and increased sensitivity to the anti-androgen enzalutamide. To better understand the clinical implications of these findings, we have evaluated fat oxidation inhibitors (etomoxir, ranolazine and perhexiline) in combination with enzalutamide in PCa cell models. We have observed a robust growth inhibitory effect of the combinations, including in enzalutamide-resistant cells and mouse TRAMPC1 cells, a more neuroendocrine PCa model. Lastly, using a xenograft mouse model, we have observed decreased tumor growth with a systemic combination treatment of enzalutamide and ranolazine. In conclusion, our results show that improved anti-cancer efficacy can be achieved by co-targeting the AR axis and fat oxidation via CPT1A, which may have clinical implications, especially in the mCRPC setting.

Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer

“…ATP and NADH are known to provide a survival advantage to cancer cells 19 and thus might contribute to cisplatin resistance as well. In concordance with our study, FAO inhibition has been shown to cause chemosensitization by limiting ATP supply in prostate cancer 43 and leukemia cells 44 .…”

Emerging role of lipid metabolism alterations in Cancer stem cells

“…1 ), whereas CPT2 is located in the inner mitochondrial membrane. CPT1A is overexpressed in prostate cancer and is associated with a high tumor grade [ 193 , 194 ]. High expression levels of CPT1A predict unfavorable clinical outcomes in AML [ 195 ] and ovarian cancer [ 196 ].…”

“…High expression levels of CPT1A predict unfavorable clinical outcomes in AML [ 195 ] and ovarian cancer [ 196 ]. Genetic or pharmacological inhibition of CPT1A exerts anti-tumor activity in prostate cancer [ 193 ], melanoma [ 197 ], breast [ 198 ], and ovarian cancer [ 196 ]. CPT1A is required for stem cell maintenance in neural stem/progenitor cells (NSPCs) [ 138 ].…”

The Potent and Selective AMPK Inhibitor BAY-3827 Shows Strong Efficacy in Androgen-Dependent Prostate Cancer Models

“…We found CPT1 family members to be down-regulated by BAY-3827, supporting a similar pathway to be implicated in prostate cancer growth. Recent knock-down and overexpression studies underline the role of CPT1 and β-oxidation in prostate cancer growth and treatment resistance [45,46]. Indeed, the determination of lipid content in treated cells showed that whereas androgen had little direct impact on lipid droplet formation, the treatment with BAY-3827 led to a signi cant accumulation of intracellular lipids, most likely due to the observed down-regulation of the CPT1 family members.…”